Cell adhesion Ephrins signaling
Ephrin-signaling The Ephrin receptor tyrosine kinases and their Ephrin ligands play a pivotal roleduring axon guidance, synaptogenesis, neuronal circuitry formation, angiogenesis and proliferation of neuronalstem cells .Ephrin receptors and Ephrin ligands transduce intracellular responses only upon bindingand clustering in the membrane . Ephrin-A receptors (Ephrin-A receptors 1-8) bindglycosylphosphatidyl-anchored Ephrin-A ligands (Ephrin-A1-5), whereas Ephrin-Breceptors (Ephrin-B receptors 1-6) bind transmembrane Ephrin-B ligands(Ephrin-B1-3) . Ephrin receptors signaling occurs through specific Guanine nucleotide exchange factors(GEFs) and therby can activate multiple Rho family GTPases including RhoA,Rac1 and CDC42. Ephrin-A stimulation of Ephrin-A receptors activates three exchange factors:Ephexin , VAV-2  and Tiam 1 . VAV-2 can also bind to Ephrin-Breceptors. In the absence of Ephrin-A stimulation, Ephrin-A receptors alternativelyengage Ephexin at the plasma membrane. This interaction induces Ephexinphosphorylation by c-Src tyrosine kinase  and this phosphorylationenhances Ephexin activity toward the GTPase RhoA and not Rac1 orCDC42 . VAV-2 is rapidly phosphorylated by c-Src upon Ephrin stimulation of bothEphrin-A receptors and Ephrin-B receptors  leading toRhoA activation . RhoA -dependent signaling in both cases leads to the growth cone retraction andcollapse. The growth cone collapse may be due to Rac1 -dependent endocytosis events.Following Ephrin-A activation, VAV-2 induces activation of Rac1which leads to actin cytoskeleton reorganization and endocytosis . Ephrin-A receptors also signal through the Rac1 exchange factor Tiam1 to promote neurite outgrowth . Ephrin-A receptor 8 localizes p110gamma isoform of phosphatidylinositol3-kinase ( PI3K cat class IB (p110-gamma) ) to the plasma membrane, therebyallowing access to lipid substrates that facilitate integrin-mediated cell adhesion. Src-like adapter protein SLAP binds to activated Ephrin-A receptor 2 and this interaction leads to the inhibiting c-Src signaling. Guanine exchange factors Kalirin and Intersectin are downstreameffectors of Ephrin-B receptors. Kalirin and Intersectin promotedendritic spine morphogenesis by modulating Rac1 and CDC42 activity,respectively . Intersectin binds to Ephrin-B receptorsindependently of activation by Ephrins, while Kalirin appear to require Ephrinstimulation. Kalirin is also phosphorylated on tyrosine residues followingEphrin-B receptors activation . The majority of Ephrin receptors negatively regulate the Ras/ MAP-kinase pathways inmost cell types . For instance, Ephrin-B receptor 2 via GTPase activatedprotein (GAP), p120GAP, down-regulates H-Ras activity and MAP kinasephosphorylation and induces neurite retraction in the some neuronal cell lines  However the phosphorylation of p120GAP by c-Src inhibites its GAPactivity . Ephrin-A1 stimulation leads to Ras-related proteinRap-1A activation  and inhibits MAPK signaling cascade bydecreasing c-Raf-1 kinase activation . Alternatively c-Raf-1can also be phosphorylated and activated by PAK1 . Recruitment ofthe adaptor proteins GRB2 and GRB10 to the activated Ephrin-B receptor1 also promotes MAP-kinase activation , . Ephrin-B receptor 1 also associates with GRB7 , thatspecifically activates RHO6, a member of Rho family GTPases, and promotes axongrowth repulsion . Ephrin-B receptor 1 and Ephrin-B receptor 2 bind adaptor protein NCK1,thereby increasing the activity of specifically Nck-interacting kinase HGK . HGK -induced JNK (stress-activated protein kinases) activationleads to the phosphorylation of Paxillin by JNK, which is essential formaintaining the dynamic cytoskeletal remodeling required for rapid cell migration . Ephrin receptors also maintain feedback mechanisms that reverse signalingthrough their Ephrin ligands . Src family kinases are responsible for Ephrin-B phosphorylation upon Ephrinreceptor engagement . The adaptor protein GRB4 linksEphrin-B to a vast signaling network that modifies cell morphology throughreorganization of the actin cytoskeleton. Phosphorylated Ephrin-B recruits thephosphotyrosine phosphatase FAP-1, that dephosphorylates the cytoplasmic domainof Ephrin-B . The GTPase-activating protein RGS3, can also transduce Ephrin-Bsignaling by catalyzing the hydrolysis of GTP to GDP in the alpha-i-subunits ofG-proteins ( G-protein alpha-i family ). This signaling mechanism has broadimplications for cell migratory behavior in different systems . Ephrin-A ligands can also induce signals that modify cell behavior. Clusteringof Ephrin-A molecules with Ephrin-A receptors recruits the Src familykinase Fyn to lipid rafts. This is accompanied by activation of MAP kinases andleading to an increase in cellular adhesion , . Inhibition of Ephrin-A signaling may be modulated at the cell surface byinduction of ligand-receptor dissociation by the metalloprotease ADAM10. Uponbinding of Ephrin-A receptors, ADAM10 cleaves Ephrin-A2ligands from the cell surface , serving two functions: 1) Ephrin-Acleavage allows Ephrin-A-receptor -bearing structures such as growth cones torevert from cellular adhesion to repulsion, and 2) ligand cleavage leads to directinhibition of receptor activation .